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Systematic review of the relationship between the 3-hydroxycotinine/cotinine ratio and cigarette dependence

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Abstract

Rationale

Individual differences in the rate of nicotine metabolism (RNM) could be related to dependence and success in stopping smoking. A range of studies have examined RNM measured by the ratio of trans-3′-hydroxycotinine and cotinine in body fluids (the ratio). A systematic review of this literature is needed to draw conclusions and identify gaps in evidence.

Objective

The aim of this study is to review evidence on the association of the ratio to cigarette dependence and its role in individual tailoring of smoking cessation pharmacotherapy.

Results

We reviewed 27 studies of the ratio related to its reliability, validity, and relationship to dependence. The ratio is a reasonably accurate proxy for RNM. There is little evidence that the ratio is related to questionnaire measures of dependence, though the existing data are limited and the ratio has been linked to smoking at night and to some aspects of smoking topography. The ratio is also only weakly associated with cigarette consumption. Its relationship to the severity of withdrawal symptoms seems also weak at best, but limited data exist. One study suggests the ratio predicts outcome of unaided quitting. Importantly, the ratio seems to predict responses both to NRT and bupropion, and thus could guide pharmacotherapy.

Conclusions

The evidence that the ratio is related to smoking behaviours and to cigarette dependence is limited, but the ratio seems to influence treatment response to two stop smoking medications. Further studies of the relationship between the ratio and cigarette dependence and trials of ratio-guided pharmacotherapy are needed.

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References

  • Al Koudsi N, Mwenifumbo JC, Sellers EM, Benowitz NL, Swan GE, Tyndale RF (2006) Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics. Eur J Clin Pharmacol 62:481–484

    Article  PubMed  CAS  Google Scholar 

  • Baker TB, Piper ME, McCarthy DE, Bolt DM, Smith SS, Kim S-Y, Colby S, Conti D, Giovino GA, Hatsukami D, Hyland A, Krishnan-Sarin S, Niaura R, Perkins KA, Toll BA, Transdisciplinary Tobacco Use Research Center (2007) Time to first cigarette in the morning as an index of ability to quit smoking: implications for nicotine dependence. Nicotine Tob Res 9(Suppl 4):S555–S570

    PubMed  Google Scholar 

  • Benowitz NL (2001) Compensatory smoking of low yield cigarettes. In: Shopland DR, Burns DM, Benowitz NL, Amacher RH (eds) Risks associated with smoking cigarettes with low machine-measured yields of tar and nicotine. Smoking and tobacco control monograph No. 13. US National Institutes of Health, National Cancer Institute, Bethesda

    Google Scholar 

  • Benowitz NL, Jacob P (1994) Metabolism of nicotine to cotinine studied by a dual stable-isotope method. Clin Pharmacol Ther 56:483–493

    Article  PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P, Jones RT, Rosenberg J (1982) Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther 221:368–372

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Pomerleau OF, Pomerleau CS, Jacob P 3rd (2003) Nicotine metabolite ratio as a predictor of cigarette consumption. Nicotine Tob Res 5:621–624

    Article  PubMed  CAS  Google Scholar 

  • Benowitz NL, Swan GE, Jacob P, Lessov-Schlaggar CN, Tyndale RF (2006) CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clin Pharmacol Ther 80:457–467

    Article  PubMed  CAS  Google Scholar 

  • Berlin I, Gasior MJ, Moolchan ET, Berlin I, Gasior MJ, Moolchan ET (2007) Sex-based and hormonal contraception effects on the metabolism of nicotine among adolescent tobacco-dependent smokers. Nicotine Tob Res 9:493–498

    Article  PubMed  CAS  Google Scholar 

  • Dempsey D, Tutka P, Jacob P, Allen F, Schoedel K, Tyndale RF, Benowitz NL (2004) Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 76:64–72

    Article  PubMed  CAS  Google Scholar 

  • Derby KS, Cuthrell K, Caberto C, Carmella SG, Franke AA, Hecht SS, Murphy SE, le Marchandl L (2008) Nicotine metabolism in three ethnic/racial groups with different risks of lung cancer. Cancer Epidemiol Biomark Prev 17:3526–3535

    Article  CAS  Google Scholar 

  • Fidler JA, Jarvis MJ, Mindell J, West R (2008) Nicotine intake in cigarette smokers in England: distribution and demographic correlates. Cancer Epidemiol Biomark Prev 17:3331–3336

    Article  CAS  Google Scholar 

  • Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991) The Fagerstrom Test for Nicotine Dependence—a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 86:1119–1127

    Article  PubMed  CAS  Google Scholar 

  • Ho MK, Mwenifumbo JC, Zhao B, Gillam EMJ, Tyndale RF (2008) A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent. Pharmacogenet Genomics 18:67–75

    Article  PubMed  CAS  Google Scholar 

  • Ho MK, Mwenifumbo JC, Al Koudsi N, Okuyemi KS, Ahluwalia JS, Benowitz NL, Tyndale RF (2009) Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers. Clin Pharmacol Ther 85:635–643

    Article  PubMed  CAS  Google Scholar 

  • Hukkanen J, Jacob P, Benowitz NL (2005) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79–115

    Article  PubMed  CAS  Google Scholar 

  • Johnstone E, Benowitz N, Cargill A, Jacob R, Hinks L, Day I, Murphy M, Walton R (2006) Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clin Pharmacol Ther 80:319–330

    Article  PubMed  CAS  Google Scholar 

  • Kandel DB, Hu MC, Schaffran C, Udry JR, Benowitz NL, Kandel DB, Hu M-C, Schaffran C, Udry JR, Benowitz NL (2007) Urine nicotine metabolites and smoking behavior in a multiracial/multiethnic national sample of young adults. Am J Epidemiol 165:901–910

    Article  PubMed  Google Scholar 

  • Kim I, Wtsadik A, Choo RE, Jones HE, Huestis MA (2005) Usefulness of salivary trans-3 ′-hydroxycotinine concentration and trans-3 ′-hydroxycotinine/cotinine ratio as biomarkers of cigarette smoke in pregnant women. J Anal Toxicol 29:689–695

    PubMed  CAS  Google Scholar 

  • Kozlowski LT, O’connor RJ, Sweeney CT (2001) Cigarette design. In: Shopland DR, Burns DM, Benowitz NL, Amacher RH (eds) Risks associated with smoking cigarettes with low machine-measured yields of tar and nicotine. Smoking and tobacco control monograph No. 13. US National Institutes of Health, National Cancer Institute, Bethesda

    Google Scholar 

  • Lea RA, Dickson S, Benowitz NL, Lea RA, Dickson S, Benowitz NL (2006) Within-subject variation of the salivary 3HC/COT ratio in regular daily smokers: prospects for estimating CYP2A6 enzyme activity in large-scale surveys of nicotine metabolic rate. J Anal Toxicol 30:386–389

    PubMed  CAS  Google Scholar 

  • Lerman C (2010) Nicotine dependence treatment: a translational approach. 12th Annual Conference Society for Resesrch on Nicotine and Tobacco Europe. Bath, UK

  • Lerman C, Tyndale R, Patterson F, Wileyto EP, Shields PG, Pinto A, Benowitz N, Lerman C, Tyndale R, Patterson F, Wileyto EP, Shields PG, Pinto A, Benowitz N (2006) Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clin Pharmacol Ther 79:600–608

    Article  PubMed  CAS  Google Scholar 

  • Lerman C, Jepson C, Wileyto EP, Patterson F, Schnoll R, Mroziewicz M, Benowitz N, Tyndale RF (2010) Genetic variation in nicotine metabolism predicts the efficacy of extended-duration transdermal nicotine therapy. Clin Pharmacol Ther 87:553–557

    Article  PubMed  CAS  Google Scholar 

  • Malaiyandi V, Goodz SD, Sellers EM, Tyndale RF (2006) CYP2A6 genotype, phenotype, and the use of nicotine metabolites as biomarkers during ad libitum smoking. Cancer Epidemiol Biomark Prev 15:1812–1819

    Article  CAS  Google Scholar 

  • Messina ES, Tyndale RF, Sellers EM (1997) A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther 282:1608–1614

    PubMed  CAS  Google Scholar 

  • Moolchan ET, Parzynski CS, Jaszyna-Gasior M, Collins CC, Leff MK, Zimmerman DL (2009) A link between adolescent nicotine metabolism and smoking topography. Cancer Epidemiol Biomark Prev 18:1578–1583

    Article  CAS  Google Scholar 

  • Mooney ME, Li ZZ, Murphy SE, Pentel PR, Le C, Hatsukami DK (2008) Stability of the nicotine metabolite ratio in ad libitum and reducing smokers. Cancer Epidemiol Biomark Prev 17:1396–1400

    Article  CAS  Google Scholar 

  • Munafo MR, Johnstone EC (2008) Genes and cigarette smoking. Addiction 103:893–904

    Article  PubMed  Google Scholar 

  • Mwenifumbo JC, Sellers EM, Tyndale RF (2007) Nicotine metabolism and CYP2A6 activity in a population of black African descent: impact of gender and light smoking. Drug Alcohol Depend 89:24–33

    Article  PubMed  CAS  Google Scholar 

  • Mwenifumbo JC, Al Koudsi N, Ho MK, Zhou Q, Hoffmann EB, Sellers EM, Tyndale RF (2008a) Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent. Hum Mutat 29:679–688

    Article  PubMed  CAS  Google Scholar 

  • Mwenifumbo JC, Lessov-Schlaggar CN, Zhou Q, Krasnow RE, Swan GE, Benowitz NL, Tyndale RF (2008b) Identification of novel CYP2A6*1B variants: the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism. Clin Pharmacol Ther 83:115–121

    Article  PubMed  CAS  Google Scholar 

  • Patterson F, Schnoll RA, Wileyto EP, Pinto A, Epstein LH, Shields PG, Hawk LW, Tyndale RF, Benowitz N, Lerman C (2008) Toward personalized therapy for smoking cessation: a randomized placebo-controlled trial of bupropion. Clin Pharmacol Ther 84:320–325

    Article  PubMed  CAS  Google Scholar 

  • Piper ME, McCarthy DE, Bolt DM, Smith SS, Lerman C, Benowitz N, Fiore MC, Baker TB (2008) Assessing dimensions of nicotine dependence: an evaluation of the Nicotine Dependence Syndrome Scale (NDSS) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM). Nicotine Tob Res 10:1009–1020

    Article  PubMed  CAS  Google Scholar 

  • Ray R, Tyndale RF, Lerman C (2009) Nicotine dependence pharmacogenetics: role of genetic variation in nicotine-metabolizing enzymes. J Neurogenet 23:252–261

    Article  PubMed  CAS  Google Scholar 

  • Rubinstein ML, Benowitz NL, Auerback GM, Moscicki AB (2008) Rate of nicotine metabolism and withdrawal symptoms in adolescent light smokers. Pediatrics 122:E643–E647

    Article  PubMed  Google Scholar 

  • Russell MAH, Stapleton JA, Feyerabend C, Wiseman SM, Gustavsson G, Sawe U, Connor P (1993) Targeting heavy smokers in general practice—randomized controlled trial of transdermal nicotine patches. Br Med J 306:1308–1312

    Article  CAS  Google Scholar 

  • Schnoll RA, Patterson F, Wileyto EP, Tyndale RF, Benowitz N, Lerman C (2009) Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: a validation study. Pharmacol Biochem Behav 92:6–11

    Article  PubMed  CAS  Google Scholar 

  • Strasser AA, Benowitz NL, Pinto AG, Tang KZ, Hecht SS, Carmella SG, Tyndale RF, Lerman CE (2011) Nicotine metabolite ratio predicts smoking topography and carcinogen biomarker level. Cancer Epidemiol Biomark Prev 20:234–238

    Article  CAS  Google Scholar 

  • Swan GE, Benowitz NL, Lessov CN, Jacob P, Tyndale RF, Wilhelmsen K (2005) Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 15:115–125

    Article  PubMed  CAS  Google Scholar 

  • Swan GE, Lessov-Schlaggar CN, Bergen AW, He YG, Tyndale RF, Benowitz NL (2009) Genetic and environmental influences on the ratio of 3 ′ hydroxycotinine to cotinine in plasma and urine. Pharmacogenet Genomics 19:388–398

    Article  PubMed  CAS  Google Scholar 

  • West R (2005) Defining and assessing nicotine dependence in humans. In: Corrigall WA (ed) Understanding nicotine and tobacco addiction. Wiley, Chichester

    Google Scholar 

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Acknowledgements

We thank Caryn Lerman and Neal Benowitz for their helpful comments on an earlier draft of this manuscript.

Conflicts of interest

PH and HM have undertaken research and consultancy for manufacturers of smoking cessation medications. OW has no conflicts of interest to declare.

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Authors and Affiliations

  1. UK Centre for Tobacco Control Studies, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AD, UK

    Oliver West, Peter Hajek & Hayden McRobbie

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  1. Oliver West
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  2. Peter Hajek
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  3. Hayden McRobbie
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Correspondence to Oliver West.

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West, O., Hajek, P. & McRobbie, H. Systematic review of the relationship between the 3-hydroxycotinine/cotinine ratio and cigarette dependence. Psychopharmacology 218, 313–322 (2011). https://doi.org/10.1007/s00213-011-2341-1

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  • DOI: https://doi.org/10.1007/s00213-011-2341-1

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